IN-VIVO STUDY OF THE ROLE OF MUSCARINIC RECEPTORS IN THE PARASYMPATHETIC CONTROL OF RABBIT COLONIC MOTILITY

The aim of the present study was to elucidate the role of the non-M(1) muscarinic receptors, in the extrinsic and intrinsic nerve control of in vivo colonic motility. Experiments were performed on the proximal colon of anaesthetized rabbits. In this species, the parasympathetic i nnervation of the proximal colon originates from the vagus nerves. The action of methoctramine and 4-diphenyl-acetoxy-N-methylpiperidine met hobromide (4-DAMP) was studied on excitatory junction potentials (EJPs ), and on inhibitory junction potentials (IJPs) elicited in smooth mus cle cells by stimulating parasympathetic efferents. The effects of the same drugs on spontaneous spiking activity were also investigated. Th e EJPs either decreased or disappeared after intra-arterial (i.a.) adm inistration of 4-DAMP (45 pg to 450 ng). In the presence of 4-DAMP, fu rther intravenous (i.v.) administration of pirenzepine (0.1 mg.kg(-1)) had facilitatory effects on the inhibitory pathway, i.e., after aboli tion of the EJPs, vagal stimulation elicited IJPs. With the highest do se of 4-DAMP, vagal stimulation immediately elicited IJPs the amplitud e of which still increased after pirenzepine. In the presence of 4-DAM P, the spontaneous spike discharge was not noticeably altered. Methoct ramine (0.37 to 75 mu g, i.a. or 50 mu g to 0.2 mg.kg(-1), i.v.) incre ased the amplitude of the EJPs, whereas it decreased that of the IJPs. In addition, at the same doses, it either initiated or increased spik e discharges that were not altered by pirenzepine up to 0.2 mg.kg(-1), i.v. The so-called rebound excitation occurring after IJPs was not af fected by methoctramine. No change in the EJP or IJP amplitude was obs erved with gallamine at sufficiently high doses to paralyse striated m uscles (up to 3 mg.kg(-1).h(-1)). It is concluded that the parasympath etic excitatory pathway to smooth muscle is blocked by 4-DAMP, whereas it is facilitated by methoctramine. 4-DAMP has no effect on the inhib itory pathway which is strongly depressed by methoctramine; however, t he fact that these two drugs have opposite effects indicates that 4-DA MP and methoctramine may act on different muscarinic receptor subtypes . In addition, the facilitatory effects of pirenzepine on IJPs observe d in animals pre-treated with 4-DAMP, indicates that the latter drug m ay act on non-M(1) and non-M(2) (presumably M(3)) muscarinic receptors . Methoctramine acts on non-M(1) and non-M(3) (presumably M(2)) recept ors. The spike discharge induced by methoctramine is presumably due to an increased release of acetylcholine, and possibly also of a non-cho linergic transmitter which has excitatory effects on smooth muscle, th e identification of which requires further investigations. The inhibit ory effects of methoctramine on IJPs indicate that non-adrenergic non- cholinergic (NANC) neurones which are inhibitory of smooth muscle are controlled by inhibitory intramural neurones, the activity of which is expressed through a muscarinic mechanism involving non-M(1) and non-M (3), presumably M(2) receptors.